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  • Review Article
  • Published:

Where the crossovers are: recombination distributions in mammals

Nature Reviews Genetics volume 5, pages 413–424 (2004)Cite this article

Key Points

  • Meiotic recombination events are distributed nonrandomly across the genome.

  • Single-molecule methods for the recovery of recombinant DNA molecules directly from sperm DNA have allowed recombination analysis to be carried out at high resolution in mammals.

  • Recent studies indicate that most meiotic recombination events (in both yeast and mammals) occur at highly localized hot spots (1–2 kb in width), whereas the bulk of the DNA is 'cold'.

  • Recombination hot spots in mice and humans are sites of initiation and resolution of both crossovers and non-crossover gene conversions.

  • Studies in model organisms, primarily budding yeast, provide direct insight into the molecular mechanisms behind hot-spot activity in mammals.

  • The primary determinant of the recombination distribution in yeast is the distribution of the double-strand breaks (DSBs) that initiate recombination. Recombination hot spots are DSB hot spots.

  • The frequency of DSBs in yeast is determined by the large-scale structural features of a chromosome as well as by local chromatin structure.

  • In principle, regional variation in crossover frequencies might also reflect differences in the likelihood that a given DSB will give rise to a crossover as opposed to a non-crossover product.

  • The fact that recombination hot spots are highly localized and separated by recombinationally 'cold' DNA is important in structuring the genome into linkage disequilibrium (LD)/haplotype blocks.

Abstract

Until recently, recombination studies in humans and mice had identified only a few anecdotal examples of crossover hot spots. Recently, the pace of discovery has accelerated. In every genomic segment that has been examined at sufficiently high resolution, recombination events have a punctate recombination distribution: they are clustered within small (1–2-kb) regions that are surrounded by large stretches of recombinationally suppressed DNA. Here, we review progress in understanding the distribution of mammalian recombination events, tie mammalian results together with informative studies in budding yeast and discuss the consequences of these findings for genome diversity and evolution.

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Figure 1: The PCR approach for recovering crossover molecules directly from sperm DNA.
Figure 2: Graphical presentation of linkage-disequilibrium data.
Figure 3: Highly localized recombination activity in the human major histocompatibility complex class II region.
Figure 4: The meiotic recombination pathway in budding yeast.
Figure 5: Nonrandom distribution of double-strand breaks in budding yeast, revealed by different resolutions of gel analysis.
Figure 6: Comparison of crossover hot-spot locations in the human and mouse major histocompatibility complex class II region.

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Acknowledgements

L.K. was supported in part by the Instrumentarium Science Foundation, the Finnish Cultural Foundation and the Osk. Huttunen Foundation. A.J.J. is supported by grants from the Royal Society, the Medical Research Council and the Wellcome Trust (UK). S.K. is supported by grants from the US National Institutes of Health and the Byrne Fund.

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Authors and Affiliations

  1. Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK

    Liisa Kauppi & Alec J. Jeffreys

  2. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Liisa Kauppi & Scott Keeney

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  1. Liisa Kauppi
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DATABASES

Entrez

ADA

ARE1

HIS4

Lmp2

LRP5

PGM1

SHOX

Spo11

TAP2

FURTHER INFORMATION

Alec Jeffreys' laboratory

GermOnline (a web database for information about germ cell biology, including meiosis)

International HapMap Project

Scott Keeney's laboratory

Glossary

HAPLOTYPE

A combination of alleles at different loci that is transmitted together from one generation to the next.

CENTIMORGAN

(cM). A measure of genetic distance. 1 cM corresponds to a 1% frequency of recombinant progeny.

CHIASMA

(pl. chiasmata). A cytologically visible physical connection between homologous chromosomes that corresponds to the position of a meiotic crossover.

LINKAGE DISEQUILIBRIUM

(LD). A measure of whether alleles at two loci coexist in a population in a nonrandom fashion. Alleles that are in LD are found together on the same haplotype more often than would be expected by chance.

MINISATELLITES

Regions of DNA in which repeat units of 6–100 bp are arranged in tandem arrays that are 0.5–30 kb in length.

LD BLOCK

A DNA segment within which markers are in significant linkage disequilibrium with each other, which implies that there is low recombination activity within the block.

GENE CONVERSION

The non-reciprocal transfer of information between homologous DNA sequences as a consequence of heteroduplex formation during recombination, which is followed by repair of mismatches in the heteroduplex.

ADMIXTURE

The mixing of two genetically differentiated populations.

ENRICHMENT-BASED ASSAY

An allele-specific hybridization method for enriching DNA molecules that carry certain allelic combinations from bulk genomic DNA.

LIKELIHOOD RATIO

The relative likelihood of obtaining observed experimental data under two different models.

ISOCHORE

A region of genomic DNA sequence in which G+C compositions are relatively uniform.

R-BANDS

A chromosome banding pattern that is produced with various staining procedures; it is reciprocal to the pattern that is produced by Giemsa staining (G-Bands).

HOLLIDAY JUNCTION

A point at which the strands of two double-stranded DNA molecules exchange partners, which occurs as an intermediate in crossing-over.

COALESCENT APPROACHES

A means of investigating the shared genealogical history of genes. A genealogy is constructed backwards in time starting with the present-day sample. Lineages coalesce when they have a common ancestor.

MEIOTIC DRIVE

Distortion of meiotic inheritance such that one allele at a heterozygous site is recovered in greater than half of the gametes (as opposed to the expected 50:50 Mendelian segregation).

PCR COLONY METHOD

A method in which individual DNA molecules are immobilized in a matrix and then subjected to PCR amplification in situ. For (haploid) sperm DNA, polymorphic sites can be typed within amplification products to yield haplotypes of chromosomal regions, allowing, in principle, the identification of recombinant molecules.

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Kauppi, L., Jeffreys, A. & Keeney, S. Where the crossovers are: recombination distributions in mammals. Nat Rev Genet 5, 413–424 (2004). https://doi.org/10.1038/nrg1346

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